Genomic Landscape of Non-Small Cell Lung Cancer in Smokers and Never-Smokers

Abstract

Summary We report the results of whole genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point mutations and over 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatic modification and DNA repair pathways were identified along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions including ROS1 and ALK as well as novel metabolic enzymes. Cell cycle and JAK-STAT pathways are significantly altered in lung cancer along with perturbations in 54 genes that are potentially targetable with currently available drugs.

The Role of Smoking Status on the Progression-Free Survival of Non-Small Cell Lung Cancer Patients Harboring Activating Epidermal Growth Factor Receptor (EGFR) Mutations Receiving First-Line EGFR Tyrosine Kinase Inhibitor Versus Platinum Doublet Chemotherapy: A Meta-Analysis of Prospective Randomized Trials

“…It has been demonstrated from comprehensive genomic profiling in adenocarcinoma between never-smokers and ever-smokers that the mutation burden (including point mutations) is at least 10-fold higher among adenocarcinoma patients who were ever-smokers [11,12]. Furthermore, these point mutations in ever-smokers tend to occur in DNA mismatch repair genes, likely leading to secondary resistance to EGFR TKI or activation of bypass pathways [12]. Finally, the frequency of transversion increased with increasing tobacco smoke exposure.…”

PyClone: statistical inference of clonal population structure in cancer

“…Despite progress in measuring allele prevalence with deep sequencing [4][5][6][7][8] , statistical approaches to cluster deep digital sequencing of mutations into biologically relevant groupings remain under-developed, with poorly understood analytical assumptions. The allelic prevalence of a mutation is a compound measure of several factors: the proportion of contaminating normal cells, the proportion of tumour cells harbouring the mutation and the number of allelic copies of the mutation in each cell, plus uncharacterized sources of technical noise.…”

Immunohistochemical detection of ROS1 is useful for identifying ROS1 rearrangements in lung cancers

“…ROS1 is fused to one of a number of genes in lung cancers, including CD74, SLC34A2, EZR, LRIG3, SDC4, TPM3, FIG (also known as GOPC), CCDC6, and KDELR2. [4][5][6][7][9][10][11][12] In these fusions, the 3 0 region of ROS1 encoding its kinase domain is fused to the 5 0 region of the respective partner gene. The fusion encodes a chimeric protein with constitutive kinase activity that initiates oncogenic intracellular signal transduction cascades.…”